Previous studies suggested that genetic variation in the HLA region of chromosome 6p may influence susceptibility to early onset periodontitis (EOP). Results of segregation analyses support the possibility that risk of EOP may be due to a single major gene. We conducted linkage analyses to evaluate the hypothesis that a gene within the HLA region significantly contributes to risk of EOP. Fifty families, with two or more close relatives affected by EOP, were ascertained in Virginia, USA and Chile. DNA was extracted from blood and a highly polymorphic marker located within the HLA region (near the Tumor Necrosis Factor Beta locus) was typed using the polymerase chain reaction. Linkage analyses were performed using a dominant model of disease transmission which is most strongly supported by previous studies. For the dominant model, assuming that EOP is a homogeneous disorder, our results statistically exclude the hypothesis that a susceptibility gene lies within 10cM (approximately 10 million bases of approximately 0.5% of the human genome. Additional analyses are planned for alternative modes of disease gene transmission. Under the assumption that EOP may actually consist of several etiologically distinct diseases having very similar clinical presentations our data still provide no support for HLA region involvement. However, our data do not statistically exclude (LOD <02.0) hypotheses of disease locus heterogeneity including models where up to half of our families contain a gene located in the HLA region which confers susceptibility to EOP. This is due to the limited power of even our relatively large collection of families and the inherent difficulties of mapping genes for disorders that have complex and heterogeneous etiologies. Additional statistical analyses, recruitment of families, and typing of flanking DNA markers are planned to more conclusively address these issues with respect to the HLA region and other candidate locations in the human genome.